Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome.

Published

Journal Article

A series of linear peptides (6a-6o) were designed based on the known non-covalent 20S proteasome inhibitors TMC-95A and compound 5 via a fragment-based approach. These compounds were synthesized and evaluated against the chymotrypsin-like activity of the human 20S proteasome. Three of them (6d, 6e and 6k) were potent inhibitors with IC50 values at the submicromolar level. These three compounds were selective to the β5-subunit and showed no obvious inhibition against trypsin-like and caspase-like activities of the human 20S proteasome. Docking study of the most potent compound 6e revealed its key interactions with the β5-subunit of the 20S proteasome. These findings have provided a new chemical template for non-covalent proteasome inhibitors, which is ready for further structural optimization to improve both potency and subunit selectivity.

Full Text

Duke Authors

Cited Authors

  • Xu, K; Wang, K; Yang, Y; Yan, D-A; Huang, L; Chen, C-H; Xiao, Z

Published Date

  • June 15, 2015

Published In

Volume / Issue

  • 98 /

Start / End Page

  • 61 - 68

PubMed ID

  • 26005024

Pubmed Central ID

  • 26005024

Electronic International Standard Serial Number (EISSN)

  • 1768-3254

Digital Object Identifier (DOI)

  • 10.1016/j.ejmech.2015.05.023

Language

  • eng

Conference Location

  • France